臺灣博碩士論文加值系統

早年的情景記憶，在各個物種中都非常容易快速地被遺忘。儘管如此，早期生活經驗已知會對發育中的個體大腦產生深遠地功能性影響。因此，是否在某些特殊情況下，發育中的大腦是否具有產生持久性記憶的功能是一個有趣的課題。再者，這些記憶是怎麼樣得以維持長久？為何早期記憶成年後無法被提取？這些記憶真的存在嗎？都是在神經科學上重要未被回答的問題。
在此研究中，我們首先探討早年記憶是否可以透過某些操弄，使其維持更持久。在成年小鼠中已被證實的行為標記假說，我們測試利用行為標記中常用的新環境探索，來促進雄性出生後20天幼年小鼠記憶的維持。以環境恐懼約制實驗模式，在特定時間內讓小鼠接受新環境刺激，我們發現其具有將環境恐懼短期記憶轉化成長期記憶的作用。此外，僅有新穎環境對於小鼠才具有行為標記的效果。我們也發現新環境探索促進長期記憶形成，取決於多巴胺D1 / D5受體的激活，並且需要在背側海馬迴CA1神經元具有新蛋白質合成的能力。然而，新環境誘導長期環境恐懼記憶具有環境專一性的，小鼠並不會因此對不同環境混淆。而我們也發現藉由環磷腺苷效應元件結合蛋白的磷酸化（p-CREB），探索新穎環境會增加海馬迴CA1錐狀神經元再次活化的比例，形成穩定的長期記憶。
其次，我們也探討成年後幼年時期記憶的影響是否存在？利用在成年齧齒類動物中已被證實存在節省法則，來評估早期恐懼記憶的影響存在與否？實驗發現幼年時期記憶影響依然存在，並合乎節省法則的理論。早期生活曾經經歷環境恐懼記憶，長大即便遺忘，會更輕鬆學習起恐懼記憶，不管是對相同形式或不同形式之恐懼行為，都有相同效果。
此等實驗結果顯示幼年時期長期記憶儲存過程中的鞏固和提取機制可能都未達成熟，利用行為標記策略可以促使形成穩定之長期記憶。此外記憶痕跡會促使往後生活中學習更加容易，印證節省法則。

Episodic memories acquired in early-life are more unstable and rapidly forgotten in both humans and non-human animals. Nonetheless, early life experiences have been documented to profoundly affect brain function throughout life span. This paradox raises the possibility that, under certain circumstances, the developing brain is capable of producing long-lasting memories. However, these long-lasting memories are disturbing to be retrieved when growing up. In this study, we first asked whether exposure to a novel environment, a process named behavioral tagging, could promote the persistence of weak memories in male juvenile mice (postnatal day 20). Here, using a contextual fear conditioning (CFC) paradigm, we showed that a weak training protocol, inducing a transient form of memory, results in long-term memory (LTM) when paired with an exploration to a novel, but not a familiar, environment occurring close in time to the training session. The promoting effect of the novel context exploration (NCE) on LTM formation dependends on the activation of dopamine D1/D5 receptors and requires new protein synthesis in the dorsal hippocampus. This NCE-induced LTM shows context specificity. Moreover, NCE increases the proportion of CA1 pyramidal neurons expressed the phosphorylation state of cyclic AMP-responsive element binding protein (pCREB) after CFC training and the degree of overlapping CA1 neuronal ensembles engaged by CFC and NCE. Second, we asked if the memories of childhood are non-existent. Using the savings theory to explore whether early-life fear memory can promote learning in adulthood, we found that the existence of influence of early-life memory traces in which promotes the similar fear memory formation in adulthood. These results provide direct support for the existence of a time-dependent behavioral tagging process and savings theory.

中文摘要 I
英文延伸摘要 IV
致謝 VII
目錄 (Table of Contents) VIII
圖目錄 (Table of Figures) IX
縮寫檢索表 X
第一章 緒論 1
1-1. 學習與記憶 2
1-2. 海馬迴CA1與記憶之相關性 3
1-3. 行為標記及細胞標記假說 4
1-4. 節省法則 6
1-5. 研究假說及目的 7
第二章 材料及方法 9
第三章 實驗結果 17
3-1. 新環境探索促使幼年小鼠形成長期恐懼環境之記憶 18
3-2. 新環境促使海馬迴合成蛋白質促進長期記憶穩定 19
3-3. 行為標記之新環境探索促進專一環境恐懼約制之長期記憶 20
3-4. 行為標記之新環境探索促使重複活化神經元之比率增高 21
3-5. 行為標記需要Dopamine D1/D5 receptor參與活化 22
3-6. 行為標記藉由提高細胞興奮性參與學習標記 23
3-7. 早期生活恐懼痕跡會促使成年後恐懼記憶學習 24
第四章 討論 26
第五章 結論 31
第六章 圖表 33
第七章 參考文獻 49

Akers, K.G., Martinez-Canabal, A., Restivo, L., Yiu, A.P., DeCristofaro, A., Hsiang, H.L., Wheeler, A.L., Guskjolen, A., Niibori, Y., Shoji, H., Ohira, K., Richards, B.A., Miyakawa, T., Josselyn, S.A. ＆ Frankland, P.W. (2014) Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science 344:598-602.
Ana M.M. ＆ Oliveira (2016) DNA methylation: a permissive mark in memory formation and maintenance. Learn Mem 23:587-593.
Andrew M. Poulos, Nehali Mehta, Bryan Lu, Dorsa Amir, Briana Livingston,Anthony Santarelli, Irina Zhuravka, and Michael S. Fanselow (2016) Conditioning- and time-dependent increases in context fear and generalization. Cold Spring Harb Perspect Biol 23:379 -385.
Arnsten, A.F.T., Ramos, B.P., Birnbaum, S.G. ＆ Taylor, J.R. (2005) Protein kinase A as a therapeutic target for memory disorders: Rationale and challenges. Trends Mol Med 11:121-128.
Axel Guskjolen, Justin W.Kenney, Juande la Parra, Bi-ru AmyYeung, Sheena A.Josselyn ＆ Paul W. Frankland (2018) Recovery of “Lost Infant Memories in Mice. Curr Biol 28:2283-2290.e3.
Brun, V.H., Otnæss, M.K., Molden, S., Steffenach, H.A., Witter, M.P., Moser, M.B. ＆ Moser, E.I. (2002) Place cells and place recognition maintained by direct entorhinal-hippocampal circuitry. Science 296:2243-2246.
Callaghan, B.L. ＆ Richardson, R. (2011) Maternal Separation Results in Early Emergence of Adult-Like Fear and Extinction Learning in Infant Rats. Behav Neurosci 125:20-28.
Campbell, B.A. ＆ Spear, N.E. (1972) Ontogeny of memory. Psychol Rev 79:215-236.
Carew, T.J. ＆ Sutton, M.A. (2001) Molecular stepping stones in memory consolidation. Nat Neurosci 4:769-711.
Cenquizca, L.A. ＆ Swanson, L.W. (2007) Spatial organization of direct hippocampal field CA1 axonal projections to the rest of the cerebral cortex. Brain Res Rev 56:1-26.
Cristian Ripoli (2016) Engrampigenetics: Epigenetics of engram memory cells. Behav Brain Res 325:297-302.
Dudai, Y., Karni, A. ＆ Born, J. (2015) The Consolidation and Transformation of Memory. Neuron 88:20-32.
Duvarci, S. (2004) Characterization of Fear Memory Reconsolidation. J Neurosci 24:9269-9275.
Frey, U. ＆ Morris, R.G.M. (1997) Synaptic tagging and long-term potentiation. Nature 385:533-536.
Groninger, L.K. ＆ Groninger, L.D. (1980) A comparison of recognition and savings as retrieval measures: A reexamination. Bull Psychon Soc 15:263-266.
Guzowski, J.F., McNaughton, B.L., Barnes, C.A. ＆ Worley, P.F. (1999) Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles. Nat Neurosci 2:1120-1124.
Han, J.H., Kushner, S.A., Yiu, A.P., Cole, C.J., Matynia, A., Brown, R.A., Neve, R.L., Guzowski, J.F., Silva, A.J. ＆ Josselyn, S.A. (2007) Neuronal competition and selection during memory formation. Science 316:457-460.
Hayne, H. (2004) Infant memory development: Implications for childhood amnesia. Dev Rev 24:33-73.
Heim, C. ＆ Nemeroff, C.B. (2001) The role of childhood trauma in the neurobiology of mood and anxiety disorders: Preclinical and clinical studies. Biol Psychiatry 49:1023-1039.
Van derHoeven, N. ＆ DeBot, K. (2012) Relearning in the Elderly: Age-Related Effects on the Size of Savings. Lang Learn 69:42-69.
Josselyn, S.A., Köhler, S. ＆ Frankland, P.W. (2015) Finding the engram. Nat Rev Neurosci 16:521-534.
Kim, J.H., McNally, G.P. ＆ Richardson, R. (2006) Recovery of fear memories in rats: Role of gamma-amino butyric acid (GABA) in infantile amnesia. Behav Neurosci 120:40-48.
Kim, J.H. ＆ Richardson, R. (2007) Immediate Post-Reminder Injection of Gamma-Amino Butyric Acid (GABA) Agonist Midazolam Attenuates Reactivation of Forgotten Fear in the Infant Rat. Behav Neurosci 121:1328-1332.
Kim, J.J., Song, E.Y. ＆ Kosten, T.A. (2006) Stress effects in the hippocampus: Synaptic plasticity and memory. Stress 9:1-11.
Kitchigina, V. (1997) Novelty-elicited, noradrenaline-dependent enhancement of excitability in the dentate gyrus. Eur J Neurosci 9:41-47.
Lechner, H.A., Squire, L.R. ＆ Byrne, J.H. (1999) 100 years of consolidation--remembering Müller and Pilzecker. Learn Mem 6:77–87.
Levy, W.B. ＆ Steward, O. (1979) Synapses as associative memory elements in the hippocampal formation. Brain Res 175:233–245.
Li, S., Callaghan, B.L. ＆ Richardson, R. (2014) Infantile amnesia: Forgotten but not gone. Learn Mem 21:135–139.
Lisman, J.E. ＆ Grace, A.A. (2005) The hippocampal-VTA loop: Controlling the entry of information into long-term memory. Neuron 16:703-713.
Liu, X., Ramirez, S., Pang, P.T., Puryear, C.B., Govindarajan, A., Deisseroth, K. ＆ Tonegawa, S. (2012) Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484:381-385.
Lu, Y., Ji, Y., Ganesan, S., Schloesser, R., Martinowich, K., Sun, M., Mei, F., Chao, M.V. ＆ Lu, B. (2011) TrkB as a Potential Synaptic and Behavioral Tag. J Neurosci 31:11762-11771.
McNaughton, B.L. ＆ Morris, R.G.M. (1987) Hippocampal synaptic enhancement and information storage within a distributed memory system. Trends Neurosci 10:408-415.
Moncada, D., Ballarini, F., Martinez, M.C., Frey, J.U. ＆ Viola, H. (2011) Identification of transmitter systems and learning tag molecules involved in behavioral tagging during memory formation. Proc Natl Acad Sci 108:12931-12936.
Moncada, D. ＆ Viola, H. (2006) Phosphorylation state of CREB in the rat hippocampus: A molecular switch between spatial novelty and spatial familiarity? Neurobiol Learn Mem 86:9-18.
Moncada, D. ＆ Viola, H. (2007) Induction of Long-Term Memory by Exposure to Novelty Requires Protein Synthesis: Evidence for a Behavioral Tagging. J Neurosci 27:7476-7481.
Nelson, T.O. (1971) Savings and forgetting from long-term memory. J Verbal Learning Verbal Behav 10:568-576.
Nelson, T.O. (1978) Detecting small amounts of information in memory: Savings for nonrecognized items. J Exp Psychol Hum Learn Mem 4:453-468.
Nomoto, M., Ohkawa, N., Nishizono, H., Yokose, J., Suzuki, A., Matsuo, M., Tsujimura, S., Takahashi, Y., Nagase, M., Watabe, A.M., Kato, F. ＆ Inokuchi, K. (2016) Cellular tagging as a neural network mechanism for behavioural tagging. Nat Commun 7:12319.
O’Carroll, C.M., Martin, S.J., Sandin, J., Frenguelli, B. ＆ Morris, R.G.M. (2006) Dopaminergic modulation of the persistence of one-trial hippocampus-dependent memory. Learn Mem 13:760-769.
Leticia Perez, Ushma Patel, Marissa Rivota, Irina E. Calin-Jageman ＆ Robert J. Calin-Jageman (2018) Savings memory is accompanied by transcriptional changes that persist beyond the decay of recall. Learn Mem 25:45-48.
Quinn, J.J., Skipper, R.A. ＆ Claflin, D.I. (2014) Infant stress exposure produces persistent enhancement of fear learning across development. Dev Psychobiol 56:1008-1016.
Redondo, R.L. ＆ Morris, R.G.M. (2011) Making memories last: The synaptic tagging and capture hypothesis. Nat Rev Neurosci 12:17-30.
Rossato, J.I., Bevilaqua, L.R.M., Izquierdo, I., Medina, J.H. ＆ Cammarota, M. (2009) Dopamine controls persistence of long-term memory storage. Science 325:1017-1020.
Rovee-Collier, C. (1999) The development of infant memory. Curr Dir Psychol Sci 8:80-85.
Rubin, D.C. ＆ Schulkind, M.D. (1997) The distribution of autobiographical memories across the lifespan. Mem Cogn 25:859-866.
Sara, S.J., Vankov, A. ＆ Hervé, A. (1994) Locus coeruleus-evoked responses in behaving rats: A clue to the role of noradrenaline in memory. Brain Res Bull 35:457-465.
Schafe, G.E. ＆ LeDoux, J.E. (2000) Memory consolidation of auditory pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J Neurosci 20:96-101.
Taubenfeld, S.M., Milekic, M.H., Monti, B. ＆ Alberini, C.M. (2001) The consolidation of new but not reactivated memory requires hippocampal C/EBPβ. Nat Neurosci 4:813-818.
Taylor, J.R., Birnbaum, S., Ubriani, R. ＆ Arnsten, A.F.T. (1999) Activation of cAMP-Dependent Protein Kinase A in Prefrontal Cortex Impairs Working Memory Performance. J Neurosci 19:RC23.
Tonegawa, S., Liu, X., Ramirez, S. ＆ Redondo, R. (2015) Memory Engram Cells Have Come of Age. Neuron 87:918-931.
Tonegawa, S., Morrissey, M.D. ＆ Kitamura, T. (2018) The role of engram cells in the systems consolidation of memory. Nat Rev Neurosci 19:485-498.
Travaglia, A., Bisaz, R., Sweet, E.S., Blitzer, R.D. ＆ Alberini, C.M. (2016) Infantile amnesia reflects a developmental critical period for hippocampal learning. Nat Neurosci 19:1225-1233.
Tsai, T.C., Huang, C.C. ＆ Hsu, K.Sen. (2019) Infantile Amnesia Is Related to Developmental Immaturity of the Maintenance Mechanisms for Long-Term Potentiation. Mol Neurobiol 56:907-919.
Tsien, J.Z., Huerta, P.T. ＆ Tonegawa, S. (1996) The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87:1327-1338.
Tulving, E. ＆ Markowitsch, H.J. (1998) Episodic and declarative memory: Role of the hippocampus. Hippocampus 8:198-204.
Vago, D.R., Wallenstein, G.V. ＆ Morris, L.S. (2014) Hippocampus. In Encyclopedia of the Neurological Sciences 1327-1338.
Vankov, A., Hervé‐Minvielle, A. ＆ Sara, S.J. (1995) Response to Novelty and its Rapid Habituation in Locus Coeruleus Neurons of the Freely Exploring Rat. Eur J Neurosci 7:1180-1187.
Whitlock, J.R., Heynen, A.J., Shuler, M.G. ＆ Bear, M.F. (2006) Learning induces long-term potentiation in the hippocampus. Science 313:1093-1097.
Wixted, J.T. (2004) The Psychology and Neuroscience of Forgetting. Annu Rev Psychol 55:235-269.
Yiu, A.P., Mercaldo, V., Yan, C., Richards, B., Rashid, A.J., Hsiang, H.L.L., Pressey, J., Mahadevan, V., Tran, M.M., Kushner, S.A., Woodin, M.A., Frankland, P.W. ＆ Josselyn, S.A. (2014) Neurons Are Recruited to a Memory Trace Based on Relative Neuronal Excitability Immediately before Training. Neuron 83:722-735.
Zhou, Y., Won, J., Karlsson, M.G., Zhou, M., Rogerson, T., Balaji, J., Neve, R., Poirazi, P. ＆ Silva, A.J. (2009) CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala. Nat Neurosci 12:1438-1443.